The goal of this research is to improve our understanding of respiratory, metabolic and cardiovascular control during exercise and to elucidate the mechanisms by which diseases limit work performance. Computerized data analysis will be used to yield accurate descriptions of dynamic physiological responses to exercise. Though exercise is the principal cardiorespiratory stress, there is no consensus on the control of exercise hyperpnea. However, evidence is accumulating which suggests that exercise hyperpnea is closely coupled to CO2 delivery to the lung. We propose to test this hypothesis during: 1) onset, 2) transition to steady-state, and 3) steady-state of exercise while perturbing certain physiologic factors. We will study effects of limiting the rate of cardiac output increase, altering the CO2 set-point, attenuating the carotid bodies with 100% oxygen, varying CO2 output by diet and continuously varying external dead space. Responses will be studied below and above the anaerobic threshold to discern the effects of metabolic acidosis. In dog, we will employ cardiopulmonary bypass techniques to separate the pulmonary from the systemic circulation, to delineate the role of pulmonary blood flow on respiration. Neurophysiologic studies in cat will be pursued in an attempt to define the reflex pathway for cardiodynamic hyperpnea. Mathematical simulations of respiratory control will aid in refining our hypotheses. A second thrust will be to study factors affecting gas exchange in health and disease. Breath-by-breath measurements of gas exchange will allow us to assess the role of arterial blood O2 content in determining the energetic pathways during exercise. The effect of altering the substrate for exercise on respiratory and cardiac demands will be determined. The role of the carotid bodies in exercise induced bronchospasm will be evaluated. The pathophysiological processes which affect both inspiratory and expiratory breathing patterns resistance to airflow, and CO2 and O2 transfer across the lungs will be studied in order to establish guidelines to assess the severity of the physiological defect in patients. This must preceed a mechanistic rationale for therapy.